Lowering an ER stress-regulated long noncoding RNA protects mice from diabetes and isolated pancreatic islets from cell death.

We investigated the role of the endoplasmic reticulum (ER) stress-regulated long noncoding RNA (lncRNA) lncMGC in pancreatic islets and the pathology of type 1 diabetes (T1D), as well as the potential of lncMGC-based therapeutics. In vivo , blood glucose levels (BGLs) and HbA1c were significantly lower in lncMGC-knockout (KO)-streptozotocin (STZ)-treated diabetic mice compared to wild-type STZ. Antisense oligonucleotides (GapmeR) targeting lncMGC significantly attenuated insulitis and BGLs in T1D NOD mice compared to GapmeR-negative control (NC). GapmeR-injected T1D Akita mice showed significantly lower BGLs compared to Akita-NC mice. hlncMGC-GapmeR lowered BGLs in partially humanized lncMGC (hlncMGC)-STZ mice compared to NC-injected mice. CHOP (ER stress regulating transcription factor) and lncMGC were upregulated in islets from diabetic mice but not in lncMGC-KO and GapmeR-injected diabetic mice, suggesting ER stress involvement . In vitro , hlncMGC-GapmeR increased the viability of isolated islets from human donors and hlncMGC mice and protected them from cytokine-induced apoptosis. Anti-ER stress and anti-apoptotic genes were upregulated, but pro-apoptotic genes were down-regulated in lncMGC KO mice islets and GapmeR-treated human islets. Taken together, these results show that a GapmeR-targeting lncMGC is effective in ameliorating diabetes in mice and also preserves human and mouse islet viability, implicating clinical translation potential.
Competing Interests: M.K. and R.N. have an issued patent and pending patent applications through City of Hope disclosing and claiming certain parts of the work detailed in this paper. These pending applications and patents include the following two families: (1) US Patent Number 10,787,664, and US Patent Application No. 16/985,779 (published as U.S. Patent Application Publication No. 2020/0407721), which both claim priority to US Provisional Application No. 62/166,533; and (2) US Patent Application No. 17/268,068 (published as US Patent Application Publication No. 2021/0310000), which claims priority to PCT/US2019/046896 and US Provisional Application No. 62/719,566.
(© 2024 The Author(s).)